Giulia Paparella

Introduction: Fibromyalgia is a heterogeneous chronic pain disorder involving both central and peripheral mechanisms. Migraine is considered a disorder with abnormal central multimodal and pain stimuli processing, whereas small fibre pathology (SFP) reflects peripheral nociceptive dysfunction. We investigated whether migraine and SFP identify distinct clinical profiles within the fibromyalgia spectrum. Methods: In this retrospective cross-sectional study, 296 patients with fibromyalgia underwent standardized clinical assessment and skin biopsy for intraepidermal nerve fibre density (IENFD). Migraine was classified as low-frequency episodic, high-frequency episodic, or chronic. Clinical severity was assessed in pain, disability, associated symptoms, and psychological domains. Multivariate analysis of covariance evaluated the independent and combined effects of migraine subtype and SFP. Subgroup analyses and correlation of clinical symptoms with IENFD were performed. Results: Migraine was diagnosed in 138 patients (46.6%; 69 low-frequency episodic, 28 high-frequency episodic, and 41 chronic migraine). Reduced IENFD was detected in 191 patients (64.5%), and its prevalence did not differ across migraine subtypes. The primary multivariate analysis of covariance did not demonstrate significant multivariate effects of migraine subtype, small fibre pathology, or their interaction. Exploratory subgroup analyses identified higher disability and associated symptom scores in patients with concomitant chronic migraine and small fibre pathology. Conclusions: Chronic migraine is associated with greater clinical burden in fibromyalgia, whereas small fibre pathology does not identify a distinct multidimensional clinical phenotype. Although patients with concomitant chronic migraine and small fibre pathology showed greater disability and associated symptom burden in exploratory analyses, these findings require confirmation in prospective studies.

Background: Primary headaches, particularly migraine, are prevalent disorders insufficiently characterized in older adults. This multicentre study evaluated headache diagnoses, focusing on migraine, across age groups in headache centers participating in the Italian Registry for Headache Disorders (RICe). Methods: Using a post hoc design, we evaluated 3477 patients enrolled at 30 headache centers (2019–2025). Patients were stratified into young adults (18–30 years), adults (31–45 years), middle‐aged (46–59 years), and elderly individuals (≥ 60 years). Demographic and clinical migraine characteristics were collected. Group differences were assessed using χ ² tests and Kruskal–Wallis ANOVAs. Results: Of 3477 patients, 644 (18.5%) were elderly, 1285 (36.9%) middle‐aged, 990 (28.5%) adults, and 558 (16.1%) young adults. Among migraine patients ( n = 3013, 86.7%), diagnoses differed across age groups ( χ ² (6) = 71.5, p < 0.001). Elderly individuals more frequently had chronic migraine ( CM ) ( z = 4.18), whereas migraine with aura was more common in young and adult patients ( z = 3.62 and 4.97, respectively). Medication‐overuse headache was more frequent in the elderly ( z = 3.56), who reported more monthly migraine days but lower pain intensity and fewer severe attacks (all p < 0.02). Stress and physical activity were common triggers. Among patients with available treatment data, some differences in prior preventive treatment patterns were observed, with more frequent use of beta‐blockers and onabotulinumtoxinA in the elderly, whereas anti‐calcitonin gene‐related peptide ( CGRP ) monoclonal antibody prescriptions did not differ across groups. Conclusions: Older adults attending headache centers more frequently presented CM, with higher attack frequency, lower pain severity, greater medication overuse, and distinct triggers, supporting tailored diagnostic and therapeutic strategies.

Background: Cutaneous allodynia is a clinical marker of central sensitization in migraine and is associated with greater migraine severity and poorer outcomes. Fibromyalgia (FM) is a frequent comorbidity of migraine that may further enhance central sensitization, whereas small fibre pathology (SFP) has been identified in a substantial proportion of FM patients. Whether FM comorbidity and peripheral small-fibre abnormalities contribute to cutaneous allodynia in patients with migraine remains unclear. We investigated cutaneous allodynia and migraine characteristics in patients with migraine with and without FM and, within the FM cohort, according to skin biopsy findings. Methods: In this retrospective cross-sectional study, 212 patients with migraine were included: 106 patients with FM who had undergone skin biopsy (65 with pathological and 41 with normal biopsy findings) and 106 patients without FM with the same sex distribution and comparable age. FM and migraine were diagnosed according to current clinical criteria. Cutaneous allodynia was assessed using a standardized clinical checklist. Skin biopsy was performed at the proximal thigh and distal leg, and SFP was defined by reduced intraepidermal nerve fibre density (IENFD). The comparison between patients with and without FM was the primary analysis; comparisons according to skin biopsy findings and correlations with IENFD were secondary analyses. Migraine characteristics, allodynia, and migraine-related disability were compared across groups. Results: The proportion of chronic migraine (CM) was similar in patients with and without FM (19.8% vs. 21.7%; p=0.866). Cutaneous allodynia was more frequent in patients with FM than in those without FM (82.1% vs. 64.2%; p=0.005), and moderate-to-severe allodynia affected 50.9% vs. 16.0% of patients, respectively (p<0.001). Median allodynia scores were 6 (interquartile range [IQR] 4-8) in patients with FM and pathological biopsy findings, 6 (3-7) in those with normal biopsy findings, and 3 (2-5) in patients without FM (p<0.001; ε2=0.133), with no difference between the two FM subgroups; allodynia scores were not associated with proximal or distal IENFD. Greater allodynia was associated with greater migraine-related disability among participants with available Migraine Disability Assessment (MIDAS) data, including after adjustment for age, headache frequency, and FM status (partial ρ=0.267, p=0.002). Conclusions: FM comorbidity identifies patients with migraine with a greater burden of cutaneous allodynia, independently of migraine chronification. This sensory hypersensitivity was not clearly related to the presence or extent of structural small-fibre loss, supporting a predominant contribution of central sensitization. Structural and functional assessments of small fibres, including trigeminal territories, may further clarify the contribution of peripheral abnormalities to migraine-related allodynia in FM.

Background: Cervical dystonia (CD) is a movement disorder with a complex pathophysiology, including cerebellar abnormalities. Transcranial alternating current stimulation (tACS), a noninvasive neuromodulation technique capable of entraining brain oscillations, can transiently modulate neuronal activity and enhance resonant rhythms. Objective: The aim of this study was to explore whether cerebellar tACS delivered at specific cerebellar‐resonant frequencies modifies fast voluntary neck movements in patients with CD and whether botulinum toxin (BoNT) therapy influences tACS effects. Methods: Eighteen patients with CD, predominantly exhibiting the torticollis phenotype, were included. Fast voluntary neck movements were objectively assessed using motion analysis during two experimental sessions: (1) pre‐BoNT and (2) 1 month after BoNT. Cerebellar tACS was applied at theta (θ), beta (β), and gamma (γ) frequencies, along with sham stimulation, while patients performed fast neck movements. Peak angular velocity and angular amplitude of both prodystonic and antidystonic movements were measured. Results: In the OFF‐BoNT state, neck (antidystonic) movements' velocity and amplitude decreased with θ‐tACS, particularly when stimulation was applied to the cerebellar hemisphere ipsilateral to the side of torticollis. BoNT ameliorated movement velocity and amplitude, but it did not change the detrimental effect of cerebellar θ oscillations on antidystonic movements. Conclusions: Driving cerebellar θ oscillations interferes with the execution of fast voluntary neck movements in CD, and BoNT therapy does not influence this effect. These findings support the view of dystonia as a network disorder in which the cerebellum plays a key role. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Bradykinesia is the hallmark sign of parkinsonism. We recently proposed redefining bradykinesia as a complex of motor abnormalities, each reflecting separate pathophysiological elements. Objective: To analyze the ‘bradykinesia complex’ in Parkinson's disease (PD) and healthy elderly individuals. Methods: We conducted a finger‐tapping kinematic analysis in 350 individuals (192 PD patients OFF medication and 158 healthy controls). A subsample of 129 patients was also tested ON medication. Group comparisons were followed by unsupervised clustering. Receiver operating characteristic (ROC) analyses defined optimal kinematic cut‐offs to detect individual motor abnormalities. We then quantified the prevalence and combinations of these features per subject. Using Bayes' theorem, we estimated the probability of PD based on the observed combination of bradykinesia features. Regression analyses served to identify predictors of kinematic alterations. Results: Patients exhibited reduced velocity and amplitude as well as altered rhythm and sequence effect compared with controls (all P‐ values < 0.001). Cluster analysis revealed substantial group overlap. ROC analyses showed that bradykinesia (movement slowness) was the most common and accurate feature for distinguishing PD, with its diagnostic power improving when combined with other motor abnormalities (hypokinesia, dysrhythmia, sequence effect). The likelihood of correctly identifying PD increased with the number of observed abnormalities, reaching up to 95% when all features were present. Levodopa improved motor performance, but the motor abnormality patterns remained unchanged. Conclusions: The detailed bradykinesia features assessment was crucial for differentiating PD individuals from controls. Diagnostic accuracy requires considering multiple motor abnormalities together, irrespective of the specific combination. Advancing our understanding of the ‘bradykinesia complex’ has clinical and pathophysiological implications. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Essential tremor (ET) is one of the most prevalent movement disorders. However, the complete understanding of ET pathophysiology remains elusive. Objective: To explore the pathophysiological role of primary motor cortex (M1) in ET, specifically exploring its neurophysiological changes and their correlation with voluntary motor abnormalities. Methods: We recruited 30 ET patients and 18 healthy controls (HC). Evaluations were conducted on patients using clinical scales. Transcranial magnetic stimulation (TMS) was used to assess M1 excitability, including motor thresholds and motor evoked potentials (MEPs) input/output curve, together with intracortical excitability measures. Long‐term potentiation (LTP)‐like plasticity of M1 was tested using intermittent theta‐burst stimulation (iTBS). Objective assessments of tremor and voluntary movement execution during finger‐tapping were conducted through kinematic analysis. Finally, we explored the potential relationship between TMS, clinical, and kinematic data. Results: Compared with HC, ET patients had lower excitability, intracortical inhibition, and lower LTP‐like plasticity of M1. ET patients also exhibited slower finger‐tapping performance compared with HC. Among ET patients, the degree of movement slowing during finger‐tapping correlated with alterations in corticospinal excitability. Specifically, reduced M1 excitability was associated with lower finger‐tapping velocity. No other correlations were found. Conclusions: The study findings reveal neurophysiological alterations of M1 in ET and demonstrate correlations between excitability measures and voluntary motor performance. These results provide novel insight into the pathophysiology of ET, emphasizing the role of M1 changes in this condition. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Over the past three decades, substantial advancements have occurred in non-invasive brain stimulation (NIBS). These developments encompass various non-invasive techniques aimed at modulating brain function. Among the most widely utilized methods today are transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES), which include direct- or alternating-current transcranial stimulation (tDCS/tACS). In addition to these established techniques, newer modalities have emerged, broadening the scope of non-invasive neuromodulation approaches available for research and clinical applications in movement disorders, particularly for Parkinson’s disease (PD) and, to a lesser extent, atypical Parkinsonism (AP). All NIBS techniques offer the opportunity to explore a wide range of neurophysiological mechanisms and exert influence over distinct brain regions implicated in the pathophysiology of Parkinsonism. This paper’s first aim is to provide a brief overview of the historical background and underlying physiological principles of primary NIBS techniques, focusing on their translational relevance. It aims to shed light on the potential identification of biomarkers for diagnostic and therapeutic purposes, by summarising available experimental data on individuals with Parkinsonism. To date, despite promising findings indicating the potential utility of NIBS techniques in Parkinsonism, their integration into clinical routine for diagnostic or therapeutic protocols remains a subject of ongoing investigation and scientific debate. In this context, this paper addresses current unsolved issues and methodological challenges concerning the use of NIBS, focusing on the importance of future research endeavours for maximizing the efficacy and relevance of NIBS strategies for individuals with Parkinsonism.

Background: Subtle parkinsonian signs, i.e., rest tremor and bradykinesia, are considered soft signs for defining essential tremor (ET) plus. Objectives: Our study aimed to further characterize subtle parkinsonian signs in a relatively large sample of ET patients from a clinical and neurophysiological perspective. Methods: We employed clinical scales and kinematic techniques to assess a sample of 82 ET patients. Eighty healthy controls matched for gender and age were also included. The primary focus of our study was to conduct a comparative analysis of ET patients (without any soft signs) and ET-plus patients with rest tremor and/or bradykinesia. Additionally, we investigated the asymmetry and side concordance of these soft signs. Results: In ET-plus patients with parkinsonian soft signs (56.10% of the sample), rest tremor was clinically observed in 41.30% of cases, bradykinesia in 30.43%, and rest tremor plus bradykinesia in 28.26%. Patients with rest tremor had more severe and widespread action tremor than other patients. Furthermore, we observed a positive correlation between the amplitude of action and rest tremor. Most ET-plus patients had an asymmetry of rest tremor and bradykinesia. There was no side concordance between these soft signs, as confirmed through both clinical examination and kinematic evaluation. Conclusions: Rest tremor and bradykinesia are frequently observed in ET and are often asymmetric but not concordant. Our findings provide a better insight into the phenomenology of ET and suggest that the parkinsonian soft signs (rest tremor and bradykinesia) in ET-plus may originate from distinct pathophysiological mechanisms.

Background: Tremor disorders have various genetic causes. Case report: A 60-year-old female with a family history of tremor presented a combined tremor syndrome, transient episodes of loss of contact and speech disturbances, as well as distal painful symptoms. Genetic screening revealed a novel heterozygous missense variant in the KCNQ2 gene. Discussion: The KCNQ2 protein regulates action potential firing, and mutations in its gene are associated with epilepsy and neuropathic pain. The identified variant, although of uncertain significance, may disrupt KCNQ2 function and also play a role in tremor pathogenesis. This case highlights the importance of genetic screening in combined tremor disorders.